Breast, colorectal, and endometrial cancers are among the top 4 leading cancer sites in women in the U.S. While environmental factors associated with these cancers have been well studied, the underlying genetic mechanisms are not well understood. The identification of susceptibility genes is important for understanding the biological basis of the causes of these cancers. This proposed study will be integrated in an ongoing NIH-funded case-cohort study conducted within the Women's Health Initiative (WHI), a large prospective study of postmenopausal women. The ongoing case-cohort study aims to measure serum levels of insulin, IGF-I, IGFBP-3, and estradiol in 900 breast, 500 colorectal, and 300 endometrial cancer cases and a sub-cohort of 900 subjects and to examine their effects on risk of the 3 cancers. The study proposed here will examine the insulin/IGF system at the genetic level in the same study subjects. There are several reasons to focus on the insulin/IGF system: (1) It has significant regulatory effects on cell proliferation and transformation. (2) Serum levels of insulin/IGF are associated with risk of several cancers. (3) It is particularly relevant to the hormone-related cancers, since insulin, IGF-I, and estradiol potentiate each other's signaling effects. On these bases, it is hypothesized that variations in the genes involved in insulin/IGF signaling may lead to altered biological effects and/or serum levels of these growth factors, and these genes could influence the susceptibility of cancer. The objectives of this study are: (1) To identify genetic variation in 9 genes that are involved in insulin/IGF signaling, namely the PI3K and MAPK pathways, and to examine their associations with risks of breast, colorectal, and endometrial cancer. (2) To examine in the subcohort if the genetic variation is associated with altered serum levels of insulin, IGF-I, and IGFBP-3. (3) To determine among the cancer cases if variation in these genes are associated with diagnostic characteristics. The secondary objective of this study is to explore the interactive effects between estradiol and variation of these genes on risk of the 3 cancers. Using existing DNA samples from the WHI, this study will apply the latest genetic analytical approach to evaluate candidate genes of 3 cancers. This genetic study, in conjunction with the ongoing serological study, will provide a comprehensive examination of the role of the insulin/IGF system in tumorigenes